The largest SWI/SNF polyglutamine domain is a pH sensor

AbstractPolyglutamines are known to form aggregates in pathogenic contexts, such as in Huntington’s disease, however little is known about their role in normal biological processes. We found that a polyglutamine domain in the SNF5 subunit of the yeast SWI/SNF complex, histidines within this sequence, and transient intracellular acidification are required for efficient transcriptional regulation during carbon starvation. We hypothesized that a pH-driven oligomerization of the SNF5 polyglutamine region is required for transcriptional reprogramming. In support of this idea, we found that a synthetic spidroin domain from spider silk, which is soluble at pH 7 but oligomerizes at pH ~ 6.3, could partially complement the function of the SNF5 polyglutamine. These results suggest that the SNF5 polyglutamine domain acts as a pH-driven transcriptional regulator.

Download Full-text

Identification of Full-Length Wild-Type and Mutant Huntingtin Interacting Proteins by Crosslinking Immunoprecipitation in Mice Brain Cortex

Journal of Huntington s Disease ◽

10.3233/jhd-210476 ◽

2021 ◽

pp. 1-13

Author(s):

Karen A. Sap ◽

Arzu Tugce Guler ◽

Aleksandra Bury ◽

Dick Dekkers ◽

Jeroen A.A. Demmers ◽

...

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Brain Cortex ◽

Full Length ◽

Biological Processes ◽

Interacting Proteins ◽

Mutant Huntingtin ◽

Wild Type ◽

Mutant Huntingtin Protein ◽

Mice Brain

Background: Huntington’s disease is a neurodegenerative disorder caused by a CAG expansion in the huntingtin gene, resulting in a polyglutamine expansion in the ubiquitously expressed mutant huntingtin protein. Objective: Here we set out to identify proteins interacting with the full-length wild-type and mutant huntingtin protein in the mice cortex brain region to understand affected biological processes in Huntington’s disease pathology. Methods: Full-length huntingtin with 20 and 140 polyQ repeats were formaldehyde-crosslinked and isolated via their N-terminal Flag-tag from 2-month-old mice brain cortex. Interacting proteins were identified and quantified by label-free liquid chromatography-mass spectrometry (LC-MS/MS). Results: We identified 30 interactors specific for wild-type huntingtin, 14 interactors specific for mutant huntingtin and 14 shared interactors that interacted with both wild-type and mutant huntingtin, including known interactors such as F8a1/Hap40. Syt1, Ykt6, and Snap47, involved in vesicle transport and exocytosis, were among the proteins that interacted specifically with wild-type huntingtin. Various other proteins involved in energy metabolism and mitochondria were also found to associate predominantly with wild-type huntingtin, whereas mutant huntingtin interacted with proteins involved in translation including Mapk3, Eif3h and Eef1a2. Conclusion: Here we identified both shared and specific interactors of wild-type and mutant huntingtin, which are involved in different biological processes including exocytosis, vesicle transport, translation and metabolism. These findings contribute to the understanding of the roles that wild-type and mutant huntingtin play in a variety of cellular processes both in healthy conditions and Huntington’s disease pathology.

Download Full-text

Mitochondrial biology and the identification of biomarkers of Huntington's disease

Neurodegenerative Disease Management ◽

10.2217/nmt-2019-0033 ◽

2020 ◽

Vol 10 (4) ◽

pp. 243-255

Author(s):

Andreas Neueder ◽

Michael Orth

Keyword(s):

Skeletal Muscle ◽

Huntington's Disease ◽

Huntington’S Disease ◽

Biological Processes ◽

Protein Species ◽

Mitochondrial Quality Control ◽

The Core ◽

Core Elements ◽

Human Material ◽

Important Challenge

Apart from finding novel compounds for treating Huntington's disease (HD) an important challenge at present consists in finding reliable read-outs or biomarkers that reflect key biological processes involved in HD pathogenesis. The core elements of HD biology, for example, HTT RNA levels or protein species can serve as biomarker, as could measures from biological systems or pathways in which Huntingtin plays an important role. Here we review the evidence for the involvement of mitochondrial biology in HD. The most consistent findings pertain to mitochondrial quality control, for example, fission/fusion. However, a convincing mitochondrial signature with biomarker potential is yet to emerge. This requires more research including in peripheral sources of human material, such as blood, or skeletal muscle.

Download Full-text

The Role of H3K4me3 in Transcriptional Regulation Is Altered in Huntington’s Disease

PLoS ONE ◽

10.1371/journal.pone.0144398 ◽

2015 ◽

Vol 10 (12) ◽

pp. e0144398 ◽

Cited By ~ 30

Author(s):

Xianjun Dong ◽

Junko Tsuji ◽

Adam Labadorf ◽

Panos Roussos ◽

Jiang-Fan Chen ◽

...

Keyword(s):

Transcriptional Regulation ◽

Huntington's Disease ◽

Huntington’S Disease

Download Full-text

SWI/SNF senses carbon starvation with a pH-sensitive low complexity sequence

10.1101/2021.03.03.433592 ◽

2021 ◽

Author(s):

J. Ignacio Gutiérrez ◽

Gregory P. Brittingham ◽

Yonca B. Karadeniz ◽

Kathleen D. Tran ◽

Arnob Dutta ◽

...

Keyword(s):

Molecular Mechanisms ◽

Ph Sensor ◽

Transcriptional Response ◽

Low Complexity ◽

Carbon Starvation ◽

Ph Sensing ◽

Ph Changes ◽

Transcriptional Reprogramming ◽

Biophysical Mechanism

AbstractIt is increasingly appreciated that intracellular pH changes are important biological signals. This motivates the elucidation of molecular mechanisms of pH-sensing. We determined that a nucleocytoplasmic pH oscillation was required for the transcriptional response to carbon starvation in S. cerevisiae. The SWI/SNF chromatin remodeling complex is a key mediator of this transcriptional response. We found that a glutamine-rich low complexity sequence (QLC) in the SNF5 subunit of this complex, and histidines within this sequence, were required for efficient transcriptional reprogramming during carbon starvation. Furthermore, the SNF5 QLC mediated pH-dependent recruitment of SWI/SNF to a model promoter in vitro. Simulations showed that protonation of histidines within the SNF5 QLC lead to conformational expansion, providing a potential biophysical mechanism for regulation of these interactions. Together, our results indicate that that pH changes are a second messenger for transcriptional reprogramming during carbon starvation, and that the SNF5 QLC acts as a pH-sensor.

Download Full-text